Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Abstract

SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsensemediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.MG1 is an ∼400-kDa member of the phosphoinositide kinaselike kinase (PIKK) family of proteins (1). Other family members include ATM, ATR, and DNA-PK, which are known regulators of DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay (NMD), a process that ensures the rapid degradation of mRNA containing premature termination codons (PTCs). It is important to eliminate these mRNAs to prevent production of truncated proteins that might interfere with the function of normal proteins in the cell. The importance of SMG1 activity for efficient NMD function is evident from markedly increased levels of PTC containing transcripts in the presence of kinase-dead SMG1 (1). Brumbaugh et al.(2) demonstrated that SMG1 is also functional in the genotoxic stress pathway. SMG1 was activated by UV and ionizing radiation (IR) to phosphorylate a p53 substrate as well as Upf1 in vitro. In cells treated with siRNA to Smg1, Chk2 and p53 were constitutively phosphorylated. Overall, the data suggested that SMG1 deficiency caused DNA damage and constitutive activation of ATM/ATR. SMG1 also plays a role in telomere stability by negatively regulating noncoding RNAs, known as telomeric repeat-containing RNA (TERRA), which associate with telomeres. Smg1 depletion increased the number of TERRA-positive chromosomes and resulted in telomere destabilization (3, 4). Additional less wellcharacterized roles for Smg1 have also been described. In Caenorhabditis elegans, using a candidate RNAi feeding screen for clones that lengthen lifespan, Masse et al. (5) reported that smg-1 inactivation increased lifespan. The effect of smg-1 inactivation on lifespan appeared to be unrelated to its NMD function but required the p53 tumor suppressor ortholog cep-1. Inactivation of smg-1 conferred resistance to oxidative stres...

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

“…Moreover, Smg1 has been showed to be involved in the predisposition to tumor formation and inflammation in Smg1 heterozygous mice; this mouse model presents elevated basal tissue and serum cytokine levels—indicating low-level inflammation—and can progress to chronic inflammation or enhanced cancer development. Therefore, this is a model of inflammation-enhanced cancer development (Roberts et al, 2013), also suggesting that Smg1 is a tumor suppressor (Du et al, 2014). To our knowledge, the possibility to target inflammation through Smg1 has never been applied to medulloblastoma until now.…”

SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways

“…22 SMG-1-knockout mice are embryonically lethal, but haploinsufficiency predisposes to a whole range of tumor formation and inflammation, demonstrating that SMG-1 is a tumor suppressor. 23 Also, diminished SMG-1 expression has been shown in HPV-positive head and neck squamous cell carcinoma and has been suggested to contribute to the enhanced response to therapy. It was previously reported that SMG-1 depletion in U2OS cells led to defects in phosphorylation of p53 on Ser15 and compromised the G 1 /S checkpoint upon treatment with IR.…”

PIKKing a way to regulate inflammation

“…More recently, mTOR has also been shown to have important roles in B cell development; mTORC1 is required for differentiation past the pre‐B cell stage, possibly as a result of regulation of glycolysis (see below for more detail) . mTORC2 in contrast is important for the development of mature B cells . Further activation of mTOR contributes to toll‐like receptor induced emergency myelopoiesis .…”

“…It is one of the least studied members of the PIKK family. Two independent mouse models have shown that complete loss of SMG1 is early embryonic lethal . SMG1 has been implicated in the control of a wide range of cellular processes including DNA damage responses, cell cycle regulation, apoptosis, hypoxia responses, and RNA stability.…”

“…SMG1 may play additional roles in regulating inflammation. Our own work has shown that mice with decreased SMG1 expression (SMG1 heterozygous mice) have increased basal inflammation and that they subsequently developed either cancer or chronic inflammatory disorders . Given that NMD can regulate up to 10% of the cellular transcriptome, dysregulation of NMD may be one mechanism by which SMG1 loss may alter the regulation of inflammation.…”